PATHOPHYSIOLOGY, PREVENTION AND TREATMENT OF AGE-RELATED OSTEOPOROSIS IN WOMEN
2. PATHOPHYSIOLOGY OF AGE-RELATED BONE LOSS AND OSTEOPOROSIS
2.2 Why do we lose bone mass as we age?
Our current understanding of the cellular mechanisms responsible for age-related bone loss are based on quantitative studies of bone cell activities in bone biopsies obtained from iliac crest or vertebral bodies of aging human population and by employing histomorphometric techniques (Frost,2001;Parfitt,1991;Frost). Bone as a tissue, is composed of bone matrix and bone cells. Bone matrix is built up of type I collagen (90%) and the remaining 10% is composed of a large number of non-collagenous proteins (e.g., osteocalcin, osteonectin, bone sialopro- teins and various proteoglycans). Non-collagenous proteins participate in the process of matrix maturation, mineralization and may regulate the functional activity of bone cells. Two main types of bone cells have been identified. Osteoblasts (bone forming cells) and osteoclasts (bone resorbing cells). These cells together with their precursor cells and associated cells (e.g., endothelial cells, nerve cells) are organized in specialized units called bone multicellular units (BMU) that perform bone remodeling activities. Bone remodeling is a bone regenerative process taking place in the adult skeleton aiming at maintaining the integrity of the skeleton by removing old bone of high mineral density and high prevalence of fatigue microfractures and replacing it with young bone of low mineral density and better mechanical properties. This process is important for the biomechanical compe- tence of the skeleton and it also supports the role of the skeleton as an active participant in the divalent ion homeostasis. Bone remodeling consists of a specific sequence of cellular events with a defined temporal sequence occurring at the same anatomical location (Figure 3). It is the same sequence in both trabecular and
INVOLUTIONAL OSTEOPOROSIS 91 cortical bone. The remodeling sequence is termed ARF sequence. “A” refers to theattraction of osteoclast precursors to specific bone sites where remodeling will take place. These sites are determined by specific mechanical needs or mechanical signals, the nature of which is not known. This is followed by activation to the osteoclast precursor cells to fuse and form functional multinucleated osteoclasts.
“R” indicates the resorptive phase, where osteoclasts remove a certain thickness of mineralized bone tissue which can be measured histomorphometrically and known as erosion depth. This phase usually lasts 4–6 weeks. “F” refers to the formative phase where osteoblasts are recruited from stem cells and precursor cells in the bone marrow. They recreate the amount of bone matrix removed by the osteoclasts and secure a proper mineralization of the newly formed osteoid tissue.
The amount of new bone formed can also be measured histomorphometrically and known as mean wall thickness. The duration of the formative phase is usually 3–4 months.
Based on understanding of bone remodeling dynamics maintenance of stable bone mass depends on: i) the balance between the osteoclastic activity indicated by the erosion depth and osteoblastic activity indicated by the mean wall thickness, and ii) the number of remodeling cycles initiated in unit time per unit bone volume (termed the activation frequency). In the young adult, there is a balance between the amount of bone removed by osteoclasts and the amount of bone formed by osteoblast and bone mass is unchanged. Both the erosion depth (Eriksen et al.,1984) and the mean wall thickness (Eriksen et al.,1984) decrease with increasing age. However, in perimenopausal women estrogen deficiency is
Resorptive period
= 6 weeks
Formative period
= 20 weeks Bone Resorption
OB OC
Bone Formation
ED MNC
SO
OS MS MWT
Figure 3. Trabecular bone remodeling following the A-R-F sequence (activation of osteoclasts, resorption by osteoclasts (OC) and mononuclear cells (MNC) and formation by osteoblasts (OB).
ED=erosion depth, MWT=mean wall thickness. OS=osteoid (unmineralized bone) surface, MS=mineralized surface
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associated with hyperactive osteoclasts and increased bone resorption compared to bone formation (Eriksen et al., 1999). On the other hand, age-related decreased mean wall thickness and impaired osteoblast functions have been observed in several histomorphometric studies in the elderly (Cohen-Solal et al., 1991;
Eriksen et al.,1990).
In addition to age-related decrease in bone mass caused by imbalance of bone resorption and bone formation, aging is associated with architectural deterioration of the skeleton as outlined above. These changes are also caused by age-related changes in bone remodeling dynamics. An age-related increase in the activation frequency (turnover) or in resorption depth will by itself threaten the integrity of the 3-dimensional trabecular network (Mosekilde,1990). During bone resorption, deep osteoclastic lacunae may hit thin trabecular structures leading to trabecular perforations. Concomitant remodeling processes on the opposite sides of thicker trabeculae may have the same consequence. The thinning of trabecular structures with age due to the imbalance between bone resorption and bone formation may also increase the risk of perforations. The consequence of this process is a progressive loss of trabecular elements, deterioration of bones three-dimensional structure and a loss of mechanical strength with age. Complex calculations from trabecular density and intertrabecular distances suggest that age-related trabecular perforations and structural changes contribute more to the age-related decrease in bone strength compared with age-related decrease in bone mass.
The above-mentioned changes in bone cells behaviour are caused by two universal factors present in the whole aging population: intrinsic age-related changes in bone cell functions and age-related changes in the endocrine system.
These universal factors interact with individual-related characteristics (e.g., genetics, environmental, behavioural) and determine the individual’s risk for developing osteoporosis.
2.2.1 Age-related changes in bone cells
Similar to other cellular compartments in the aging body, bone cells undergo a multitude of age-related changes that contribute to bone loss. The available data suggest that decreased cell proliferation capacity of osteogenic stem cells is the rate limiting factor for bone formation with age (Stenderup et al.,2003). The aging microenvironment may also contribute to the age-related decreased bone formation since sera obtained from old persons (a surrogate for the aging microenvironment of bone) exerted inhibitory effects on osteoblast differentiation of osteoprogenitor cells compared to sera obtained from young persons (Kassem et al. Bone, 2006, in press).
2.2.2 Age-related changes in the endocrine system
Aging is associated with several changes in the endocrine system which in turn affects different organs in the body including the skeleton. Some of the best studied endocrine systems with respect to their impact on bone are: sex steroids,
INVOLUTIONAL OSTEOPOROSIS 93
Figure 4. Age-changes in the endocrine system and its contribution to the observed age-related bone loss.25(OH)D=25-hydroxyvitamin D, 1,25(OH)2D=1,25-dihydroxyvitamin D. PTH=parathyroid hormone. GH=growth hormone, IGF=insulin-like growth factor. Ca=calcium. All the changes in the endocrine system lead finally to increase+in osteoclastic bone resorption and inhibition−of osteoblastic bone formation leading to remodelling imbalance and bone loss
parathyroid hormone and growth hormone (GH)/insulin-like growth factor (IGF) system (Figure 4).
A. Sex steroids In women, aging is associated with marked changes in serum levels of estrogen but not androgens. Total estradiolE1decreases from 221 pmol/l in young women to 133 pmol/l in elderly women and estroneE2from 338 pmol/l in young to 78 pmol/l in elderly women while a slight drop in testosterone (T) levels decrease from 1.4 in young to 1.1 nmol/l in elderly women (Khosla et al.,1998).
Estrogen deficiency and bone loss in women
The rapid decrease of estrogen metabolites in the postmenopausal period leads to increased bone turnover, osteoclast activity (Eriksen et al.,1999) and consequently increased bone resorption compared to bone formation leading to bone loss. The molecular basis of increased osteoclastic activity resulting from E deficiency has recently been a topic of intensive investigation. E deficiency has been shown to increase the production of osteoclast-activating cytokines (IL-1, TNF-, IL-6) and E treatment led to the inhibition of their production (Pacifici,1996). Also, E is capable for induction of apoptosis in osteoclasts and shortening of osteoclast life span
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(Hughes et al., 1996). The direct effects of E on osteoblastic cell functions are less clear.
B. Parathyroid hormone Age-related secondary hyperparathyroidism is caused by age-related impaired mechanisms of calcium conservation. With increasing age, intestinal calcium absorption is impaired because of decreased production of 1,25-dihydroxyvitamine D (Slovik et al., 1981). Also, an age-related increased urinary calcium excretion (urinary calcium leak) has been reported (Heshmati et al., 1998). Recently, Riggs et al., (Riggs et al., 1998) have suggested that the age- related secondary hyperparathyroidism and impaired mechanisms of calcium conser- vation and homeostasis are caused by the effects of E deficiency on intestine and kidneys.
C. Growth hormone and insulin-like growth factors (IGF) Serum levels of GH reach its peak in late puberty, and afterwards a pronounced age-related decline in serum levels which can be explained by decreased secretion rate (Finkelstein et al., 1972;Ho et al.,1987) and increased clearance rate (Iranmanesh et al.,1991). Serum concentrations of IGF-I largely parallel serum GH with a peak at puberty and a decrease with ageing. Serum IGF-I, but not IGF-II correlates closely to 24-hour integrated GH secretion (Florini et al.,1985). Similarly, serum levels of IGF-I and not IGF-II decrease with age in both men and women (Florini et al.,1985;Copeland et al.,1990;Bennett et al.,1984). The age-related decline in GH and IGF-I parallels the age-related decline in bone mass suggesting that changes in serum GH and IGF- I are responsible for the age-related bone-loss. However, administration of GH to healthy elderly persons was unable to restore and only increased bone mass slightly (Rudman et al., 1990). Therefore, it seems unlikely that GH and IGF are major factors contributing to the skeletal phenotype of senescence except in subgroup of osteoporotic patients with abnormally low levels of the hormones.
2.2.3 Genetic, environmental and individual risk factors
Peak bone mass and the rate of bone loss are affected by a multitude of factors including genetic, behavioral and dietary. They are also affected by diseases and medications received by the persons throughout their life history.
Several studies have shown that part of the varaitions of bone mass of adult skeleton can be explained by polymorphic traits in a number of key extracellular matrix components (collagen type I), hormones receptors (vitamin D receptors, ER, AR, PTH/PTHrp receptors), cytokines (OPG, RANKL, TGF-). However, the relative contributions of each of these polymorphic traits to age-related bone loss need to be determined (Nguyen et al.,2000;Ralston,2002).
Smoking, large alcohol intake, exercise levels, decreased in muscle strength due to aging or specific neuromuscular disorders, diet and diseases affecting the skeleton (e.g. hyperthyroidism, anorexia nervosa, chronic exposure to glucocorti- coids) are some of a long list of factors that are capable of affecting bone mass and
INVOLUTIONAL OSTEOPOROSIS 95 skeletal integrity. These factors can interact with the universal mechanisms of age- related bone loss described above and determine the individual risk for developing